P552: TREATMENT OUTCOMES IN NEWLY DIAGNOSED, UNTREATED PATIENTS WITH TP53-MUTATED ACUTE MYELOID LEUKEMIA: A SYSTEMATIC LITERATURE REVIEW AND META-ANALYSIS
Authors: N. G. Daver, S. Iqbal, C. Renard, R. J. Chan, K. Hasegawa, H. Hu, P. Tse, J. Yan, M. J. Zoratti, F. Xie, G. Ramsingh
Journal: HemaSphere (2022)

Background:TP53 mutations are present in 10% to 15% of patients with acute myeloid leukemia (AML) and are associated with resistance to therapy and poor outcomes. Currently available frontline therapies for TP53-mutated AML include intensive chemotherapy (IC), hypomethylating agents (HMAs), and venetoclax combined with HMA (VEN+HMA). Aims: To describe response and survival outcomes associated with IC, HMAs, and VEN+HMA in newly diagnosed, untreated patients with TP53-mutated AML. Methods: EMBASE and MEDLINE were systematically searched to identify prospective and retrospective studies that reported complete remission (CR), CR with incomplete hematologic recovery (CRi), median overall survival (OS), event-free survival (EFS), or duration of response (DOR) outcomes in patients with TP53-mutated AML treated with IC, HMAs, or VEN + HMA. Screening and data extraction were conducted independently and in duplicate by 2 reviewers. Response outcomes (CR and CRi) were pooled using random-effects models, and the median of medians method was used for time-related outcomes (OS, EFS, DOR). Results: From the 3006 abstracts identified (May 20, 2021), 17 publications (12 studies: 6 randomized controlled trials, 2 single-arm trials, and 4 retrospective studies) satisfied the inclusion criteria (Table). The percentage of patients achieving CR was highest with IC (43%; 95% CI, 30%-56%; N=133), followed by VEN+HMA (33%; 95% CI, 22%-47%; N=54;) and HMA (21%; 95% CI, 7%-49%; N=14). The CRi rate was highest with VEN+HMA (20%; 95% CI, 12%-33%; N=54), followed by IC (6%; 95% CI, 1%-20%; N=35). No studies reported CRi outcomes for HMA alone. The rates of CR/CRi were 49% (95% CI, 37%-60%; N=121) for VEN+HMA, 46% (95% CI, 39%-53%; N=200) for IC, and 13% (95% CI, 2%-48%; N=28) for HMA alone. The median OS was similarly low across the 3 treatments: 6.5 months for IC (95% CI, 5.1-8.5 months; N=155), 6.2 months for VEN+HMA (95% CI, 5.2-7.2 months; N=73), and 6.1 months for HMA (95% CI, 4.9-7.2 months; N=34). The median EFS was 3.7 months (95% CI, 1.6-5.7 months; N=133) with IC. The median DOR was 3.5 months (N=35) with IC and 5.0 months (95% CI, 3.5-6.5 months; N=54) with VEN+HMA. No studies reported EFS for HMA alone or VEN+HMA or DOR for HMA alone. Table. - Outcomes in newly diagnosed, untreated adult patients with TP53-mutated AML treated with IC, HMA, and VEN+HMA ICstudies Total, N Outcome(95% CI) HMAstudies Total, N Outcome(95% CI) VEN+HMAstudies Total, N Outcome(95% CI) CR rate 2 133 0.43(0.30-0.56) 1 14 0.21(0.07-0.49) 2 54 0.33(0.22-0.47) CRi rate 1 35 0.06(0.01-0.2) 0 - - 2 54 0.20(0.12-0.33) CR/CRi rate 4 200 0.46(0.39-0.53) 2 28 0.13(0.02-0.48) 4 121 0.49(0.37-0.60) Median OS, months 3 155 6.5(5.1-8.5) 2 34 6.1(4.9-7.2) 2 73 6.2(5.2-7.2) Median EFS, months 2 133 3.7(1.6-5.7) 0 - - 0 - - Median DOR, months 1 35 3.5(not reported) 0 - - 2 54 5.0(3.5-6.5) Summary/Conclusion: CR, CR/CRi, DOR, and median OS were modest across all treatments for newly diagnosed, untreated patients with TP53-mutated AML. Limitations of this analysis include low study and patient numbers for some interventions, the lack of direct trial comparisons, and that CR/CRi outcomes were not reported separately for DOR. The findings of this review highlight the significant unmet need for this very difficult-to-treat population.